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Synergistic Effects of Interleukin-1 , Interleukin-6, and Tumor

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Synergistic Effects of Interleukin-1 , Interleukin-6, and Tumor Synergistic Effects of Interleukin-1␤, Interleukin-6, and Tumor Necrosis Factor-␣: Central Monoamine, Corticosterone, and Behavioral Variations Karen Brebner, M.S., Shawn Hayley, M.S., Robert Zacharko, Ph.D., Zul Merali, Ph.D., and Hymie Anisman, Ph.D. The proinflammatory cytokines interleukin-1␤ (IL-1␤), IL-6, these cytokines synergistically increased plasma corticosterone and tumor necrosis factor-alpha (TNF-␣) influence levels. Although IL-1␤ and TNF-␣ provoked variations of neuroendocrine activity, promote central neurotransmitter amine turnover in the hypothalamus, locus coeruleus, and alterations, and induce a constellation of symptoms collectively central amygdala, synergistic effects were not evident in this referred to as sickness behaviors. These cytokines may also elicit respect. Nevertheless, in view of the central amine variations anxiety and anhedonia, and have been associated with induced by the cytokines, it is suggested that immune psychological disturbances in humans. In the present activation may come to influence complex behavioral processes, investigation, systemic IL-1␤ and TNF-␣ dose-dependently as well as affective state. [Neuropsychopharmacology and synergistically disrupted consumption of a highly 22:566–580, 2000] © 2000 American College of palatable food source (chocolate milk), possibly reflecting Neuropsychopharmacology. Published by Elsevier Science Inc. anorexia or anhedonia engendered by the treatments. As well, KEY WORDS: Cytokines; Corticosterone; Dopamine; alterations may impact on immune activity (Blalock Monoamines; Neurochemical; Norepinephrine; Serotonin; 1994; Dunn 1990; Rivier 1993; Rothwell et al. 1997). It Synergism; IL-1; IL-6; TNF-␣ has been posited that, among other things, the immune It is clear that interactions occur between the immune, system acts like a sensory organ informing the brain of endocrine, central, and autonomic nervous systems. Im- antigenic challenge (Blalock 1994) and that immune ac- munological manipulations (or products of an activated tivation may be interpreted by the CNS as a stressor immune system, e.g., cytokines) may affect neuroendo- (Anisman and Merali 1999; Dunn 1990). Further, cyto- crine and central neurotransmitter processes, and con- kines may be part of a regulatory loop that, by virtue of versely, neuroendocrine and central neurotransmitter effects on CNS functioning, might influence behavioral outputs and may even contribute to the symptoms of behavioral pathologies, including mood and anxiety- From the Institute of Neuroscience, Carleton University, Ottawa, related disorders (Anisman and Merali 1999). Indeed, Ontario, Canada (KB, SH, RZ, HA); and School of Psychology and in humans, depression was associated with variations Department of Cellular and Molecular Medicine (ZM), University of ␤ ␤ Ottawa, Ottawa, Ontario, Canada. of plasma cytokines, including interleukin-1 (IL-1 ), Address correspondence to: Hymie Anisman, Ph.D., Life Sciences IL-1 receptor antagonist (IL-1Ra), IL-2, soluble IL-2 re- Research Building, Carleton University. Ottawa, Ontario K1S 5B6, ceptors, IL-6, and soluble IL-6 receptors (Anisman et al. Canada. Received January 28, 1999; revised May 10, 1999; accepted 1998; Maes 1995; Maes et al. 1995; Muller and Ackenheil December 6, 1999. 1998). NEUROPSYCHOPHARMACOLOGY 2000–VOL. 22, NO. 6 © 2000 American College of Neuropsychopharmacology Published by Elsevier Science Inc. 0893-133X/00/$–see front matter 655 Avenue of the Americas, New York, NY 10010 PII S0893-133X(99)00166-9 NEUROPSYCHOPHARMACOLOGY 2000–VOL. 22, NO. 6 Synergistic Effects of Cytokines 567 Cytokines and bacterial endotoxins, such as li- provoke central neurochemical changes, and may thus popolysaccharide (LPS), induce a constellation of ap- also impact on behaviors associated with particular parently adaptive behavioral changes, collectively re- transmitter alterations. Indeed, IL-1␤ was found to act ferred to as “sickness behaviors” (Dantzer et al. 1996). synergistically with a mild stressor to increase For instance, these agents induce fever, reduce social monoamine variations within the prefrontal cortex, nu- exploration, sexual behaviors, and food consumption cleus accumbens and dorsal hippocampus (Merali et al. (Bluthe et al. 1992; Johnson et al. 1996; Plata-Salaman 1997). Moreover IL-1␤ plus TNF-␣ acted synergistically 1988; Plata-Salaman et al. 1988; O’Reilly et al. 1987). In to influence neurotoxicity in mixed neuronal/glial cell addition, endotoxins may induce anxiogenic-like effects cultures containing IFN␥ (Jeohn et al. 1998 ), to stimu- (Lacosta et al. 1999) and disrupt responding for reward- late mitogen-activated protein kinase (Lu et al. 1997), ing brain stimulation (Borowski et al. 1998), possibly re- and along with IL-6 to provoke TNF-␣ mRNA expres- flecting anhedonic effects elicited by the immune chal- sion in rat C6 glioma cells (Gayle et al. 1998). However, lenge. The behavioral effects of endotoxin and unlike these effects, to our knowledge, no such syner- cytokine treatment are paralleled by increased hypo- gisms have been reported with respect to central thalamic-pituitary-adrenal (HPA) activity, as reflected monoamine functioning. The present investigation eval- by increased activity of corticotropin releasing hor- uated the individual and synergistic effects of IL-1␤, IL-6, mone (CRH) and elevated plasma ACTH and corticos- and TNF-␣ on an index of illness behavior (consump- terone levels (Kakucksa et al. 1993; Tilders et al. 1993). tion of a highly preferred food substance, i.e., chocolate Inasmuch as cytokines elicit several effects similar to milk), plasma corticosterone, and central monoamine those of LPS, it has been assumed that at least some of levels and turnover. the endotoxin effects involve IL-1␤, or this cytokine acting conjointly or synergistically with IL-6 and/or TNF-␣ (Dunn 1992a; Ebisui et al. 1994; Long et al. 1990; EXPERIMENTS 1–3 Zanetti et al., 1992; Zhou et al. 1996). Indeed, IL-1␤ and IL-6 synergistically increased plasma corticosterone Individual Effects of IL-1␤, IL-6 and TNF-␣ (Zhou et al. 1996) and ACTH (Matta et al. 1992; Subjects. Male CD-1 mice, eight weeks of age were Perlstein et al. 1991), whereas IL-1␤ and TNF-␣ syner- obtained from Charles River Inc, Laprairie, Quebec, gistically stimulated IL-11 through the production of Canada. After arrival at the facility, mice were housed prostaglandin-E2 in rheumatoid synovial fibroblasts in groups of four and acclimated to the laboratory for at (Mino et al. 1998). As well, IL-1␤ and TNF-␣ synergisti- least two weeks. Room temperature was maintained at cally reduced blood glucose levels (Vogel et al. 1991), 21ЊC, and lighting was maintained on a 12 hr light/ social exploration (Bluthe et al. 1994), and food intake dark cycle (lights on at 0800). One week prior to the be- (Plata-Salaman et al. 1996; Sonti et al. 1996; Yang et al. ginning of the experiments, mice were separated into 1994), and increased the levels of inducible nitric oxide individual polypropylene cages with wire mesh lids synthase (Kuemmerle 1998). and maintained ad libitum on pellet mouse chow (5075 In addition to their peripheral actions, IL-1␤, IL-6, Rodent diet Autoclaved; Ralston Purina) and tap water. and TNF-␣ exert numerous central neurochemical ef- All procedures of the present investigation met the fects. In this respect, IL-1␤ increases NE turnover in the guidelines of the Carleton University Animal Ethics PVN, as well as other hypothalamic nuclei (Dunn Committee, as well as the guidelines set forth by the 1992b; Palazzolo and Quadri, 1992; Shintani et al. 1995). Canadian Council on Animal Care. At all times, efforts Likewise, IL-1␤ increases the accumulation of the sero- were made to minimize the number of animals used, tonin metabolite 5-HIAA in the hypothalamus (Dunn and to minimize animal suffering. 1992b) as well as prefrontal cortex and hippocampus (Zalcman et al. 1994), and may alter hypothalamic DA Procedure. In order to avoid confounding effects re- utilization (Masana et al. 1990; Palazzolo and Quadri lated to the stress of food deprivation, in the present in- 1992; Shintani et al. 1993). Furthermore, IL-1␤ increased vestigation sickness was evaluated by assessing con- in vivo hippocampal serotonergic functioning (Merali et sumption of a highly preferred food substance. Prior to al. 1997; Song et al. 1999), and that of hypothalamic NE, cytokine administration, mice were given free access to 5-HT, and DA release (Shintani et al. 1995). While con- chocolate milk for one hour each day during the light siderably less attention has focused on IL-6 and TNF-␣, phase (1000–1100 hrs). Bottles were weighed at the be- these cytokines have been shown to alter central ginning and end of the session in order to determine monoamine levels, albeit to a lesser degree than that ob- consumption. Following the establishment of a steady served after IL-1␤ treatment (Mefford et al. 1991; Zalc- rate of drinking (three consecutive days over which man et al. 1994). consumption varied by less than 10%), mice received an In addition to their individual effects, it is conceiv- acute i.p. injection of either IL-1␤, IL-6, or TNF-␣ (at one able that IL-1␤, IL-6, and TNF-␣ may synergistically of several doses) or vehicle (pyrogen-free sterile saline) 568 K. Brebner et al. NEUROPSYCHOPHARMACOLOGY 2000–VOL. 22, NO. 6 in three independent experiments. Consumption was by HPLC using a modification of the method of Seegal measured beginning 45 min (in the case of IL-1␤ and IL-6) et al. (1986). Tissue punches were sonicated in a homog- or 30 min (in the case of TNF-␣) following injection. Re- enizing solution comprised of 14.17g monochloracetic covery data was collected 24 hr following cytokine ad- acid, 0.0186 g disodium EDTA, 5.0 ml methanol, and ministration. 500 ml H20. Using a waters M-6000 pump, guard col- ␤ ␮ Recombinant human IL-1 was kindly provided by umn, radial compression column (5 , C18 reverse Dr. Craig Reynolds (Biological Response Modifiers Pro- phase, 8 mm ϫ 10 cm), and a three cell coulometric elec- gram; National Cancer Institute, Frederick, MD, USA. trochemical detector (ESA Model 5100 A), 20 ␮l of the Produced by E.I.
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